Neisseria gonorrhoeae is the etiologic agent of the sexually transmitted infection, gonorrhea. Antibiotics are the mainstay in treating infections, but widespread resistance in N. gonorrhoeae, most notably emerging resistance to ceftriaxone, may soon result in strains that are untreatable with current antibiotics. Thus, new antibiotics against novel targets are desperately needed to stem the tide of resistant bacteria that are becoming a major threat to public health. The goal of this proposal is to optimize inhibitors of LpxC, an essential enzyme in the lipid A biosynthetic pathway, for treatment of N. gonorrhoeae infections. Preliminary data demonstrate that LpxC inhibitors are bactericidal for N. gonorrhoeae and are largely unaffected by established resistance mechanisms. Further development of these novel compounds will be achieved by (1) lead optimization of LpxC inhibitors, (2) evaluation of pharmacokinetic and pharmacodynamic properties of lead compounds, and (3) evaluation of antibiotic efficacies in a mouse model of infection. At the completion of this project, we anticipate having one or more LpxC inhibitors with good pharmacokinetic and pharmacodynamic properties that are potent and efficacious against N. gonorrhoeae both in vitro and in vivo. These studies would meet a number of benchmarks required for assembling an investigational new drug application to the FDA for approval of a new class of antibiotics for treatment of N. gonorrhoeae and other Gram-negative infections. PUBLIC HEALTH RELEVANCE: The sexually transmitted infection (STI) gonorrhea, caused by the Gram-negative bacterium, Neisseria gonorrhoeae, is the second most common STI in the U.S., with over 350,000 cases reported in 2007. N. gonorrhoeae is a major cause of pelvic inflammatory disease, can increase the possibility of ectopic pregnancy, and is associated with an increased rate of transmission of HIV. Historically, N. gonorrhoeae has become resistant to nearly all of the antibiotics that have been used to treat infections, including penicillin, tetracycline, and fluoroquinolones. The minimum inhibitory concentrations (MICs) of the sole antibiotic recommended for treatment of gonococcal infections, ceftriaxone, have increased rapidly in the last decade, and it is only a matter of time before the emergence of fully resistant strains of N. gonorrhoeae renders all of the current treatment options obsolete. This proposal addresses this unmet global public health need by optimizing inhibitors of LpxC, which catalyzes an essential step in lipid A biosynthesis to treat gonococcal infections, including those caused by multidrug-resistant strains. Successful completion of this proposal has the potential to develop a new class of antibiotics that target an unexploited essential pathway in Gram-negative bacteria.